Interferon-γ Stimulates Monocyte Chemotactic Protein-1 Expression by Monocytes

Monocyte chemotactic protein (MCP-1) is a specific monocyte chemoattractant and activating factor produced by both immune cells (mononuclear phagocytes and lymphocytes) and non-immune cells (parenchymal and stromal cells). In order to define the conditions under which human monocytes express MCP-1, monocytes were exposed to IFN-γ, IL- lβ, TNF-α, IL-4 or PHA under serum free conditions. There was no significant MCP-1 production by monocytes following exposure to IL-lβ, TNF-α or IL-4. In contrast, stimulation with IFN-γ resulted in a dose dependent increase in MCP-1 protein and mRNA expression. Simultaneous stimulation with IFN-γ and IL-1β or TNF-α resulted in no further increase in MCP-1 production. It is concluded that IFN-γ, primarily a product of TH1 T lymphocytes, stimulates the expression of MCP-1 by monocytes

Phosphotyrosine Signaling Analysis in Human Tumors Is Confounded by Systemic Ischemia-Driven Artifacts and Intra-Specimen Heterogeneity

Tumor protein phosphorylation analysis may provide insight into intracellular signaling networks underlying tumor behavior, revealing diagnostic, prognostic or therapeutic information. Human tumors collected by The Cancer Genome Atlas program potentially offer the opportunity to characterize activated networks driving tumor progression, in parallel with the genetic and transcriptional landscape already documented for these tumors. However, a critical question is whether cellular signaling networks can be reliably analyzed in surgical specimens, where freezing delays and spatial sampling disparities may potentially obscure physiologic signaling. To quantify the extent of these effects, we analyzed the stability of phosphotyrosine (pTyr) sites in ovarian and colon tumors collected under conditions of controlled ischemia and in the context of defined intratumoral sampling. Cold-ischemia produced a rapid, unpredictable, and widespread impact on tumor pTyr networks within 5 minutes of resection, altering up to 50% of pTyr sites by more than 2-fold. Effects on adhesion and migration, inflammatory response, proliferation, and stress response pathways were recapitulated in both ovarian and colon tumors. In addition, sampling of spatially distinct colon tumor biopsies revealed pTyr differences as dramatic as those associated with ischemic times, despite uniform protein expression profiles. Moreover, intratumoral spatial heterogeneity and pTyr dynamic response to ischemia varied dramatically between tumors collected from different patients. Overall, these findings reveal unforeseen phosphorylation complexity, thereby increasing the difficulty of extracting physiologically relevant pTyr signaling networks from archived tissue specimens. In light of this data, prospective tumor pTyr analysis will require appropriate sampling and collection protocols to preserve in vivo signaling features.National Institutes of Health (U.S.) (Grant U24 CA159988

Physics at the e+ e- Linear Collider

A comprehensive review of physics at an e+e- Linear Collider in the energy range of sqrt{s}=92 GeV--3 TeV is presented in view of recent and expected LHC results, experiments from low energy as well as astroparticle physics.The report focuses in particular on Higgs boson, Top quark and electroweak precision physics, but also discusses several models of beyond the Standard Model physics such as Supersymmetry, little Higgs models and extra gauge bosons. The connection to cosmology has been analyzed as well.Comment: 179 pages, plots and references updated, version to be published at EPJ

Shifting Winds: Using Ancestry DNA to Explore Multiracial Individuals\u27 Patterns of Articulating Racial Identity

This study explored how genotype information affects identification narratives of multiracial individuals. Twenty-one multiracial individuals completed individual interviews before and after receiving a DNA analysis to clarify their genetically based racial ancestry. Based on results, this article proposes patterns of articulating racial identity by multiracial individuals. Four patterns extend evolving research in multiracial identification, namely (1) the individual articulates a monoracial identity; (2) the individual articulates one identity, but this can shift in response to various conditions; (3) the individual articulates an extraracial identity, opting out of traditional categories applied to race; and (4) the person distinguishes traditional categories of race from culture and owns the two identities in different ways. Implications of these findings are discussed. First, adding new ancestry DNA information further muddles the neat categories of race, consistent with the view of race as socially constructed. Second, results emphasize the fluidity of identification for multiracial individuals. Third, DNA information challenges the neat percentages people tend to associate with their backgrounds. Particularly for younger multiracial individuals, there was less of a sense that race was a real thing and more that culture played a big part in how they saw themselves

Comparing the immune response to a novel intranasal nanoparticle PLGA vaccine and a commercial BPI3V vaccine in dairy calves

peer-reviewedBackground There is a need to improve vaccination against respiratory pathogens in calves by stimulation of local immunity at the site of pathogen entry at an early stage in life. Ideally such a vaccine preparation would not be inhibited by the maternally derived antibodies. Additionally, localized immune response at the site of infection is also crucial to control infection at the site of entry of virus. The present study investigated the response to an intranasal bovine parainfluenza 3 virus (BPI3V) antigen preparation encapsulated in PLGA (poly dl-lactic-co-glycolide) nanoparticles in the presence of pre-existing anti-BPI3V antibodies in young calves and comparing it to a commercially available BPI3V respiratory vaccine. Results There was a significant (P < 0.05) increase in BPI3V-specific IgA in the nasal mucus of the BPI3V nanoparticle vaccine group alone. Following administration of the nanoparticle vaccine an early immune response was induced that continued to grow until the end of study and was not observed in the other treatment groups. Virus specific serum IgG response to both the nanoparticle vaccine and commercial live attenuated vaccine showed a significant (P < 0.05) rise over the period of study. However, the cell mediated immune response observed didn’t show any significant rise in any of the treatment groups. Conclusion Calves administered the intranasal nanoparticle vaccine induced significantly greater mucosal IgA responses, compared to the other treatment groups. This suggests an enhanced, sustained mucosal-based immunological response to the BPI3V nanoparticle vaccine in the face of pre-existing antibodies to BPI3V, which are encouraging and potentially useful characteristics of a candidate vaccine. However, ability of nanoparticle vaccine in eliciting cell mediated immune response needs further investigation. More sustained local mucosal immunity induced by nanoparticle vaccine has obvious potential if it translates into enhanced protective immunity in the face of virus outbreak

Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine. A post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial

Background: The PRESTO study of non-invasive vagus nerve stimulation (nVNS; gammaCore®) featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, we examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication. Methods: Patients recorded pain intensity for treated migraine attacks on a 4-point scale. Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity. We also assessed the percentage of attacks that required rescue medication and pain-free rates stratified by pain intensity at treatment initiation. Results: A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min (nVNS, 32.2%; sham, 18.5%; P = 0.020), 60 min (nVNS, 38.8%; sham, 24.0%; P = 0.017), and 120 min (nVNS, 46.8%; sham, 26.2%; P = 0.002) after the first attack. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack (nVNS, 59.3%; sham, 41.9%; P = 0.013) and all attacks (nVNS, 52.3%; sham, 37.3%; P = 0.008). When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min (all attacks: nVNS, 37.0%; sham, 21.2%; P = 0.025) and 120 min (first attack: nVNS, 50.0%; sham, 25.0%; P = 0.018; all attacks: nVNS, 46.7%; sham, 30.1%; P = 0.037). Conclusions: This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events. Trial registration: ClinicalTrials.gov identifier: NCT02686034

Severe Acute Respiratory Infection-Preparedness: Protocol for a Multicenter Prospective Cohort Study of Viral Respiratory Infections

OBJECTIVES: Respiratory virus infections cause significant morbidity and mortality ranging from mild uncomplicated acute respiratory illness to severe complications, such as acute respiratory distress syndrome, multiple organ failure, and death during epidemics and pandemics. We present a protocol to systematically study patients with severe acute respiratory infection (SARI), including severe acute respiratory syndrome coronavirus 2, due to respiratory viral pathogens to evaluate the natural history, prognostic biomarkers, and characteristics, including hospital stress, associated with clinical outcomes and severity. DESIGN: Prospective cohort study. SETTING: Multicenter cohort of patients admitted to an acute care ward or ICU from at least 15 hospitals representing diverse geographic regions across the United States. PATIENTS: Patients with SARI caused by infection with respiratory viruses that can cause outbreaks, epidemics, and pandemics. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measurements include patient demographics, signs, symptoms, and medications; microbiology, imaging, and associated tests; mechanical ventilation, hospital procedures, and other interventions; and clinical outcomes and hospital stress, with specimens collected on days 0, 3, and 7-14 after enrollment and at discharge. The primary outcome measure is the number of consecutive days alive and free of mechanical ventilation (VFD) in the first 30 days after hospital admission. Important secondary outcomes include organ failure-free days before acute kidney injury, shock, hepatic failure, disseminated intravascular coagulation, 28-day mortality, adaptive immunity, as well as immunologic and microbiologic outcomes. CONCLUSIONS: SARI-Preparedness is a multicenter study under the collaboration of the Society of Critical Care Medicine Discovery, Resilience Intelligence Network, and National Emerging Special Pathogen Training and Education Center, which seeks to improve understanding of prognostic factors associated with worse outcomes and increased resource utilization. This can lead to interventions to mitigate the clinical impact of respiratory virus infections associated with SARI